Bispecific antibodies: The next generation of targeted inflammatory bowel disease therapies

Targeting various disease pathways using monoclonal antibodies (mAbs) has transformed the treatment paradigm for inflammatory bowel disease (IBD), with these agents exhibiting improved efficacy over corticosteroids or immunosuppressive therapies. Antibodies targeting tumor necrosis factor α (TNF-α) were the first approved biologics for IBD, followed by the more recent approval of antibodies targeting the α4β7 integrin heterodimer and ustekinumab, which targets the p40 subunit of interleukin-23. Current efforts are focused on the development of additional biologics targeting these known and other newly discovered pathways. Still significant unmet needs remain, as a large proportion of patients either fail to achieve remission or fail to respond altogether. Both Crohn's disease and ulcerative colitis are complex and heterogeneous diseases with several molecular pathways involved in disease pathophysiology. We propose an additional therapeutic approach to the treatment of IBD, bispecific antibodies (BsAbs), which combine two distinct binding specificities within a single biologic to allow the simultaneous targeting of multiple disease-causing cytokines or pathways. Although primarily used in oncology thus far, the unique combinatorial mechanism of action of BsAbs may provide new therapeutic options for a broad range of clinical applications, including autoimmune and inflammatory diseases. This review will discuss the current status of BsAb development in general and potentially therapeutic application in IBD.     

Inflammatory bowel disease following solid organ transplantation

Inflammatory bowel disease (IBD) is a T cell driven inflammatory condition of the gut. Following solid organ transplantation (SOT), de novo IBD has been reported despite anti-T cell therapy for the prevention of organ rejection. This paradox is illustrated with a case report, highlighting the difficult diagnostic criteria, the potential role of Damage or Pathogen Associated Molecular Pattern Molecules [DAMPs and PAMPs] that drives aspects of ongoing inflammation within the transplanted organ as well as the intestine, and the therapeutic strategies applied. Recurrent IBD is more common than de novo IBD following transplantation, with cumulative risks ten years after orthotopic liver transplantation of 70% and 30%, respectively. Furthermore, the annual incidence of de novo IBD following solid organ transplantation has been estimated to be 206 cases/100,000 or ten times the expected incidence of IBD in the general population (approximately 20 cases/100,000). The association of IBD with other autoimmune conditions such as primary sclerosing cholangitis and autoimmune hepatitis, both common indications for liver transplantation, may play a contributory role, particularly in view of the observation that IBD is more common following liver transplant than other solid organ transplants. Recurrent IBD following transplant appears to run a more aggressive course than de novo IBD, with a higher proportion requiring colectomy for medically refractory disease. Risk factors that have been associated with development of post-transplant IBD include acute CMV infection and the use of tacrolimus.     

Clinical Aspects and Pathophysiology of Inflammatory Bowel Disease

The chronic inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, are recognized as important causes of gastrointestinal disease in children and adults. In this review we delineate the clinical manifestations and diagnostic features of IBD. In addition, we summarize important recent advances in our understanding of the immune mediators of intestinal inflammation. This information has led to new therapeutic approaches in IBD. Further, we discuss the considerable data that point to the significance of genetic factors in the development of IBD and the genetic loci which have been implicated through genome-wide searches. The commensal bacterial flora also appears to be a critical element, particularly in regards to Crohn's disease, although the precise role of the bacteria in the disease manifestations remains unclear. Current investigations promise to yield fresh insights in these areas.     

The potential beneficial role of faecal microbiota transplantation in diseases other than Clostridium difficile infection

This review gives an outline of the indications for faecal microbiota transplantation (FMT) for diseases other than Clostridium difficile (C. difficile) infection. The remarkable efficacy of FMT against C. difficile infection has already been demonstrated. The use of FMT for other diseases, such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and metabolic syndrome, is now being evaluated. The currently available data suggest that FMT might be beneficial for IBD (including ulcerative colitis and, to some extent, Crohn's disease), IBS, and insulin resistance. Several randomized clinical trials are currently being performed, and data are eagerly awaited. A new field of research for the implementation of FMT is the eradication of pathogenic and multiresistant enteric microorganisms. A few animal studies have been performed within this field, but hardly any research data from human studies are available at present.     

The role of inflammatory bowel disease susceptibility loci in multiple sclerosis and systemic lupus erythematosus

To date, three loci have been validated to confer susceptibility to inflammatory bowel disease (IBD): the CARD15/NOD2 gene, the discs large homolog 5 gene (DLG5), and the IBD5 locus on 5q31 (IBD5). We have explored the possibility that these loci may also be associated with susceptibility to two other chronic inflammatory diseases, multiple sclerosis (MS) and systemic lupus erythematosus (SLE). As the CARD15 risk alleles had previously been assessed in our collection of 496 MS trios, we focused our efforts on the DLG5 risk allele and the IBD5(risk) haplotype (IBD5(risk)) for MS. While there is no evidence of association within our MS sample with either of these polymorphisms, screening of 1027 subjects with SLE suggests that IBD5(risk) may have a modest contribution to disease risk in the subset of SLE subjects without lupus nephritis. In addition, a pooled analysis of existing published and unpublished data in 1305 cases of SLE genotyped for the CARD15 risk alleles suggests that only the CARD15(908R) IBD risk allele may have a strong effect on risk of SLE. Our data, therefore, suggest that both the CARD15 gene and the IBD5 locus may have a role as general susceptibility loci for certain common, genetically complex inflammatory diseases.     

Neutrophil–T cell crosstalk in inflammatory bowel disease

Neutrophils are the most abundant leucocytes in human blood, promptly recruited to the site of tissue injury, where they orchestrate inflammation and tissue repair. The multifaceted functions of neutrophils have been more appreciated during the recent decade, and these cells are now recognized as sophisticated and essential players in infection, cancer and chronic inflammatory diseases. Consequently, our understanding of the role of neutrophils in inflammatory bowel disease (IBD), their immune responses and their ability to shape adaptive immunity in the gut have been recognized. Here, current knowledge on neutrophil responses in IBD and their capacity to influence T cells are summarized with an emphasis on the role of these cells in human disease.     

Mitogen activated protein kinases: a role in inflammatory bowel disease?

Since their discovery more than 15 years ago, the mitogen activated protein kinases (MAPK) have been implicated in an ever‐increasingly diverse array of pathways, including inflammatory signalling cascades. Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are characterized by the perpetual production of inflammatory mediators. Research into the transduction pathway behind this over‐production has highlighted the potential mediating role for the MAPKs and their related signalling components. This review highlights some of the research into the role for the MAPKs and their related signalling proteins in influencing the progression of IBD.     

Mannan-binding lectin (MBL) gene polymorphisms in ulcerative colitis and Crohn's disease

The inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC), are complex multifactorial traits involving both environmental and genetic factors. Mannan-binding lectin (MBL) plays an important role in non-specific immunity and complement activation. Point mutations in codons 52, 54 and 57 of exon 1 of the MBL gene are associated with decreased MBL plasma concentrations and increased susceptibility to various infectious diseases. If these MBL mutations could lead to susceptibility to putative IBD-etiological microbial agents, or could temper the complement-mediated mucosal damage in IBD, MBL could function as the link between certain microbial, immunological and genetic factors in IBD. In this study, we investigated the presence of the codon 52, 54 and 57 mutations of the MBL gene in 431 unrelated IBD patients, 112 affected and 141 unaffected first-degree relatives, and 308 healthy control individuals. In the group of sporadic IBD patients (n = 340), the frequency of the investigated MBL variants was significantly lower in UC patients when compared with CD patients (P = 0.01) and with controls (P = 0.02). These results suggest that MBL mutations which decrease the formation of functional MBL could protect against the clinical development of sporadic UC, but not of CD. This could be explained by the differential T-helper response in both diseases.     

Targets for new immunomodulation strategies in inflammatory bowel disease

Crohn's disease (CD) and ulcerative colitis (UC), the major forms of inflammatory bowel diseases (IBD) in human beings, are characterized by damage to the intestinal epithelium and deeper layers, which is caused by an excessive immune response directed against normal constituents of the gut microflora. In both IBD, the diseased tissue is heavily infiltrated with several subsets of leukocytes that produce huge amounts of inflammatory cytokines whose profiles varies not only between CD and UC but also during the evolution of the same disease. These recent discoveries together with the demonstration that the inhibition of some soluble cytokines is not beneficial in IBD have contributed to delineate new scenarios by which tissue damage is induced and perpetuated. We here review some of the major immunological defects documented in IBD and discuss why compounds inhibiting soluble cytokines were not beneficial in patients and how we can optimize therapeutic strategies with biologics.     

Damage-associated molecular patterns and their role as initiators of inflammatory and auto-immune signals in systemic lupus erythematosus

Damage-associated molecular patterns (DAMPs) are endogenous molecules that are released into the extracellular space under conditions of activation, cellular stress, or tissue damage. These molecules are recognized by pattern-recognition receptors (PRRs) and can induce inflammation and immune responses in the absence of infection. An increasing number of DAMPs have been linked to the pathogenesis of many auto-immune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis, and systemic sclerosis (SSc); as they promote the maturation/activation of different immune cells and pro-inflammatory cytokines production associated with these diseases. Several studies suggest that the loss of tolerance to self-antigens in these diseases could be due to continuous exposure to DAMPs. Thus, understanding the mechanisms of sterile inflammation triggered by DAMPs is important to elucidate novel therapeutic strategies for the treatment of various auto-immune diseases through inhibition or modulation the expression of these molecules. To this end, this review describes different DAMPs, their molecular characteristics, their modifications, and the receptors through which they activate an immune response while considering their role in the pathogenesis of various auto-immune diseases.     

Probiotics and inflammatory bowel disease

Inflammatory bowel disease (IBD) is characterised by a chronic dysregulation of the inflammatory response in the gastrointestinal tract. While the pathogenesis is unclear, studies have demonstrated that the gastrointestinal tracts of patients with IBD are populated with increased levels of adherent and pathogenic bacteria. This evidence, combined with growing data accumulated from genetic studies as well as animal models of IBD, indicates that an aberrant response to altered enteric flora plays a significant role in the disease process. Current therapies for IBD have been directed towards the development of anti-inflammatory agents and immunomodulators to attenuate the inflammatory response in the gastrointestinal tract. Antibiotics are also partially effective in the treatment of IBD, presumably by altering the bowel flora. However, it is clear from clinical trials that immunomodulators and antibiotics are not effective in a large proportion of patients with IBD and other therapeutic alternatives need to be pursued. Probiotics are microbial supplements capable of recolonising the bowel with non-pathogenic strains of bacteria or yeast. Probiotics have long been shown to be beneficial in both infectious and non-infectious digestive disorders. Growing evidence indicates that probiotics may be effective in the treatment of specific clinical IBD conditions. This article addresses the current evidence for the role of enteric flora in the pathogenesis of IBD and the clinical evidence supporting the use of probiotics in specific clinical IBD conditions.     

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

Rare, monogenetic diseases present unique models to dissect gene functions and biological pathways, concomitantly enhancing our understanding of the etiology of complex (and often more common) traits. Although inflammatory bowel disease (IBD) is a generally prototypic complex disease, it can also manifest in an early‐onset, monogenic fashion, often following Mendelian modes of inheritance. Recent advances in genomic technologies have spurred the identification of genetic defects underlying rare, very early‐onset IBD (VEO‐IBD) as a disease subgroup driven by strong genetic influence, pinpointing key players in the delicate homeostasis of the immune system in the gut and illustrating the intimate relationships between bowel inflammation, systemic immune dysregulation, and primary immunodeficiency with increased susceptibility to infections. As for other human diseases, it is likely that adult‐onset diseases may represent complex diseases integrating the effects of host genetic susceptibility and environmental triggers. Comparison of adult‐onset IBD and VEO‐IBD thus provides beautiful models to investigate the relationship between monogenic and multifactorial/polygenic diseases. This review discusses the present and novel findings regarding monogenic IBD as well as key questions and future directions of IBD research.     

Tuftsin phosphorylcholine—a novel compound harnessing helminths to fight autoimmunity

The distinction that in areas where helminthic infections are common, autoimmune diseases are less prevalent, led to the investigation of immune modulatory properties of helminths and their derivatives. Such are phosphorylcholine (PC) moieties which are a component of secreted products of helminths. PC has been broadly studied for its attenuating effects on the human immune system. In an attempt to develop a novel therapeutic small molecule for the treatment of autoimmune conditions, we have conjugated PC with tuftsin, a natural immunomodulatory tetrapeptide, to create TPC. Herein, we review our findings regarding the effects of TPC in murine models of three autoimmune diseases—systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and rheumatic arthritis (RA), as well as ex-vivo samples from giant cell arteritis (GCA) patients. In all four disease models examined, TPC was shown to attenuate the inflammatory response by reducing expression of pro-inflammatory cytokines and altering the phenotype of T cell expression. In murine models, TPC has further produced a significant improvement in clinical disease scores with no significant side effects noted. Our findings suggest TPC presents promising potential as a novel therapeutic agent for the effective treatment of various autoimmune conditions.     

Classical and recent advances in the treatment of inflammatory bowel diseases

Crohn''s disease (CD) and ulcerative colitis (UC) are intestinal disorders that comprise the inflammatory bowel diseases (IBD). These disorders have a significant effect on the quality of life of affected patients and the increasing number of IBD cases worldwide is a growing concern. Because of the overall burden of IBD and its multifactorial etiology, efforts have been made to improve the medical management of these inflammatory conditions. The classical therapeutic strategies aim to control the exacerbated host immune response with aminosalicylates, antibiotics, corticosteroids, thiopurines, methotrexate and anti-tumor necrosis factor (TNF) biological agents. Although successful in the treatment of several CD or UC conditions, these drugs have limited effectiveness, and variable responses may culminate in unpredictable outcomes. The ideal therapy should reduce inflammation without inducing immunosuppression, and remains a challenge to health care personnel. Recently, a number of additional approaches to IBD therapy, such as new target molecules for biological agents and cellular therapy, have shown promising results. A deeper understanding of IBD pathogenesis and the availability of novel therapies are needed to improve therapeutic success. This review describes the overall key features of therapies currently employed in clinical practice as well as novel and future alternative IBD treatment methods.     

Stem cell treatment for Crohn’s disease

While stem cell-based treatments have been established as a clinical standard of care for some conditions, such as hematopoietic stem cell transplants for cancer, the scope of potential stem cell-based therapies has expanded in recent years due to advances in stem cell research, paving the way for the increasing utilization of stem cell therapies in severe immune-mediated diseases including inflammatory bowel diseases (IBDs) and, in particular, Crohn’s disease. Both hematopoietic stem cells and mesenchymal (stromal) stem cells are considered to be of potential therapeutic benefit in immune-mediated conditions. A growing body of experimental and clinical evidence shows that hematopoietic stem cell transplant induces long-lasting remission in a majority of patients with active severe Crohn’s disease refractory to drug treatments, and the differential effect of potent immunosuppression and immune reconstitution in this setting is under evaluation. Mesenchymal stem cells have been shown to exert immunomodulatory action on various types of immune-mediated diseases, and in experimental models of IBD, but evaluation of the potential efficacy of this therapy in IBD is still in the early stages.     

Maladie de Crohn et génétique : connaissances actuelles

Crohn's disease as ulcerative colitis are the main chronic inflammatory bowel diseases (IBD) in the developed countries of the world with an estimated prevalence of 1/250. Morbidity of these diseases are important and some patients live with a considerable symptom burden despite medical treatment. In 2001, mutations in the gene CARD15 (also named NOD2) have been identified and involved in susceptibility for Crohn's disease. Theses findings have played an important role to elucidate the leading role of innate immune response in the bowel and in understanding the pathogenesis of IBD and have helped to identify potential targets for therapeutic intervention. This paper summarizes the important knowledge acquisitions in the physiopathology of Crohn's disease. It underlines the important environmental, immunologic and genetic components leading to this multifactorial disease.     

Diagnostic value, clinical utility and pathogenic significance of reactivity to the molecular targets of Crohn's disease specific-pancreatic autoantibodies

Pancreatic autoantibodies (PAB) giving characteristic staining patterns of the exocrine pancreas by indirect immunoflourescence appear to be specific markers of Crohn's disease (CrD), being present in approximately 30% of patients with CrD and in less than 5% of patients with ulcerative colitis (UC). Some studies have suggested that PAB are associated with specific disease phenotypes and that their detection may be of clinical significance. Thorough investigation of the role of PAB in the immunopathogenesis of inflammatory bowel diseases (IBD) has been hampered due to the lack of identity of their antigenic targets. The recent identification of the pancreatic zymogen granule protein 2 (GP2) as the major target of PAB has led to the development of an enzyme immunoassay that helps determine the diagnostic and clinical relevance of antigen-specific immune responses. Recent studies have demonstrated that GP2 is expressed on the apical surface of intestinal membranous cells of the follicle-associated epithelium, and is essential for host-microbial interaction and the initiation of bacteria-specific mucosal immune responses. This review critically discusses recent reports investigating the diagnostic and clinical utility of GP2-specific autoantibody responses in patients with IBD. Hints towards a better understanding of the immunogenicity of GP2 are also provided.     

Spondylitis-psoriasis-enthesitis-enterocolitis-dactylitis-uveitis-peripheral synovitis (SPEED-UP) treatment

Axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), psoriasis, inflammatory bowel disease (IBD), and noninfectious uveitis form a distinct group among the immune mediated inflammatory diseases. Thus, many patients suffer from more than one of these disease manifestations. Here, we will use the term spondylitis-psoriasis-enthesitis-enterocolitis-dactylitis-uveitis-peripheral synovitis (SPEED-UP) spectrum disease. The aim is to review the new targeted pharmacological treatment options for all these diseases. All biological or targeted synthetic drugs with U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMA) approval for any of the diagnoses axSpA, PsA, psoriasis, IBD, or non-infectious uveitis were included. Some of the drugs have documented efficacy in more than one of the diseases, e.g. tumor necrosis factor (TNF) inhibitors. However, other drugs are particularly effective for a specific inflamed tissue and approved in only one or two of the disease entities, e.g. abatacept for peripheral arthritis and vedolizumab for inflammatory bowel disease. This contributes with bedside to bench understanding of the immunology underlying this disease spectrum and provides clinicians with an overview that can assist stratified treatment decisions. We hope that this review will help guide clinicians to speed up treatment of patients with this disease spectrum.